Transient receptor potential (TRP) channels are non-selective cation channels that are activated by a variety of stimuli. Numerous members of the ion channel family have been identified to date, including the cold-menthol receptor, also called TRP M8 (MCKEMY, D. D., et al “Identification of a cold receptor reveals a general role for TRP channels in thermosensation”, Nature, pp 52-58, Vol. 416 (6876)). Collectively, the TRP channels and related TRP-like receptors connote sensory responsivity to the entire continuum of thermal exposure, selectively responding to threshold temperatures ranging from noxious hot through noxious cold as well as to certain chemicals that mimic these sensations. Specifically, TRP M8 is known to be stimulated by cool to cold temperatures as well as by chemical agents such as menthol and icilin, which may be responsible for the therapeutic cooling sensation that these agents provoke.
TRP M8 is located on primary nociceptive neurons (A-delta and C-fibers) and is also modulated by inflammation-mediated second messenger signals (ABE, J., et al. “Ca2+-dependent PKC activation mediates menthol-induced desensitization of transient receptor potential M8”, Neurosci Lett, 2006, pp 140-144, Vol. 397(1-2); PREMKUMAR, L. S., et al. “Downregulation of Transient Receptor Potential Melastatin 8 by Protein Kinase C-Mediated Dephosphorylation”, J. Neurosci, 2005, pp 11322-11329, Vol. 25(49)). The localization of TRPM8 on both A-delta and C-fibers may provide a basis for abnormal cold sensitivity in pathologic conditions wherein these neurons are altered, resulting in pain, often of a burning nature (KOBAYASHI, K., et al. “Distinct expression of TRPM8, TRPA1 and TRPV1 mRNAs in rat primary afferent neurons with a c-fibers and colocalization with Trk receptors” J Comp Neurol, 2005, pp 596-606, Vol. 493(4), 596-606; ROZA, C. et al., “Cold sensitivity in axotomized fibers of experimental neuromas in mice”, Pain, 2006, pp 24-36, Vol 120(1-2); XING, H., et al., “Chemical and Cold Sensitivity of Two Distinct populations of TRPM8-Expressing Somatosensory Neurons”, J Neurophysiol, 2006, pp 1221-1230, Vol. 95(2)). Cold intolerance and paradoxical burning sensations induced by chemical or thermal cooling closely parallel symptoms seen in a wide range of clinical disorders and thus provide a strong rationale for the development of TRP M8 modulators as novel antihyperalgesic or antiallodynic agents. TRP M8 is also known to be expressed in the brain, lung, bladder, gastrointestinal tract, blood vessels, prostate and immune cells, thereby providing the possibility for therapeutic modulation in a wide range of maladies.
There remains a need in the art for TRPM8 antagonists that can be used to treat a disease or condition in a mammal in which the disease or condition is affected by the modulation of TRPM8 receptors, such as chronic or acute pain, or the diseases that lead to such pain, and pulmonary or vascular dysfunction.